The Data Monitoring Committee for the phase 3 KEYNOTE-A18 clinical trial has announced that the study met one of its primary end points.
A progression-free survival (PFS) improvement has been demonstrated with the combination of pembrolizumab (Keytruda), external beam radiotherapy (EBRT), and concurrent chemotherapy in patients with newly diagnosed, high-risk, locally advanced cervical cancer. The result was clinically meaningful and statistically significant, meeting a primary end point of the phase 3 KEYNOTE-A18 trial (NCT04221945).1
Results come from the prespecified interim analysis of the trial, which also showed an encouraging trend toward overall survival (OS) improvement, a coprimary end point of the study. Further, there were no new safety signals observed with pembrolizumab, and the safety profile overall was as expected. Follow-up for OS is ongoing in the study, and full findings will be presented at an upcoming medical meeting.
“Patients with high-risk locally advanced cervical cancer often have a poor prognosis, with more than half of patients experiencing disease recurrence within two years. However, there have been limited new treatment advances for these patients beyond the current standard of care in the last 20 years,” said Domenica Lorusso, MD, PhD, principal investigator of the study, lead investigator for ENGOT, and associate professor of Obstetrics and Gynecology at the Catholic University of Rome, in a press release. “These results are very encouraging and support the use of pembrolizumab combined with the current standard of care in locally advanced cervical cancer to help address the need for new treatment options beyond chemoradiotherapy alone.”
KEYNOTE-A18 is a randomized, double-blind study of pembrolizumab with chemoradiotherapy vs placebo plus chemoradiotherapy. In the pembrolizumab-containing arm, the PD-L1 inhibitor will be dose at 20 mg and administered via intravenous (IV) infusion on day 1 of each 3-week cycle, with pembrolizumab 400 mg IV on day of each 6-week cycle to follow for an additional 15 cycles. Concurrent chemotherapy is introduced at the 3rd week of treatment and consists of cisplatin 40 mg/m2 IV once a week for 5 or 6 weeks in combination with EBRT. EBRT is followed by brachytherapy doses at 80 Gy if volume-directed and 75 Gy if point-directed.2
Over 1000 patients withnewly diagnosed, high-risk, locally advanced cervical cancer will be included in the study and evaluated for the primary end points as well as the secondary efficacy end points of PFS by blinded independent central review (BICR), investigator-assessed PFS at 24 months, BICR-assessed PFS at 24 months, OS at month 36, complete response rate at week 12 by investigator assessment, CR rate at week 12 by BICR, investigator-assessed objective response rate (ORR), BICR-assessed ORR, investigator-assessed PFS in the PD-L1-positive population, BICR-assessed PFS in the PD-L1-positive population, investigator-assessed OS in the PD-L1-positive group, and OS by BICR in the PD-L1-positive.
The secondary safety end points in the study include, change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score, change from baseline in EORTC Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer, the number of patients with adverse events (AEs), and the number of patients who discontinue study treatment because of AEs.
Patients eligible to enroll are those with newly diagnosed, high-risk, locally advanced cervical cancer who had histologically confirmed disease. No patients can be previously treated with surgery, radiation, or systemic therapy. All patients are required to have a ECOG performance status of 0 or 1, tissue sample available for biopsy, radiographic evaluable disease per RECIST v1.1, and adequate organ function 7 days before starting study treatment.
“The role of [pembrolizumab] is already established in certain patients with persistent, recurrent or metastatic cervical cancer, and these results reinforce our research efforts in earlier stages of disease where there is a greater potential for better outcomes,” said Gursel Aktan, MD, PhD, vice president, global clinical development, Merck Research Laboratories, in the press release.1 “We are encouraged by these results that show treatment with Keytruda significantly improved progression-free survival for patients with newly diagnosed high-risk locally advanced cervical cancer.”
1. Merck announces phase 3 KEYNOTE-A18 trial met primary endpoint of progression-free survival (PFS) in patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. July 19, 2023. Accessed July 19, 2023. https://tinyurl.com/47t8jmxd
2. Study of chemoradiotherapy with or without pembrolizumab (MK-3475) for the treatment of locally advanced cervical cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047). ClincalTrials.gov. Updated November 25, 2022. Accessed July 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04221945